Florey Department of Neuroscience and Mental Health, University of Melbourne, Melbourne, VIC, Australia

Department of Biophysics, Columbia University, New York, United States of America

Department of Neuroscience, Columbia University, New York, United States of America

BackgroundBrain-Derived Neurotrophic Factor (BDNF) is a
promoter of neuronal plasticity. The BDNF gene
Val66Met polymorphism disrupts activity-dependent secretion of BDNF and has
been, variably, associated with anxiety and mood disorders. It has been
suggested that stress hormones, which further down-regulate transcription of
BDNF, may mediate the involvement of the Val66Met polymorphism in these
disorders. However, this hypothesis lacks experimental validation. We therefore
sought to model the long-term effects of chronic stress by using a novel Val66Met
knock-in mouse that is genetically modified to express
human BDNF (hBDNF) via endogenous mouse promoters.

ResultsAt baseline, memory of fear was disrupted in hBDNFMet/Met mice
relative to hBDNFVal/Val controls. However, this phenotype was
reversed by a BDNF-CORT interaction which selectively enhanced memory of fear in
hBDNFMet/Met mice. While extinction learning was unaffected at
baseline, chronic CORT exposure selectively increased rate of extinction learning in hBDNFVal/Met
and hBDNFMet/Met mice relative to hBDNFVal/Val
controls. There was no BDNF-mediated anxiety-like phenotype on the LDB. The FST
revealed a depressive-like phenotype of hBDNFMet/Met mice at
baseline, while the chronic CORT treatment selectively increased the
depressive-like behavior of hBDNFVal/Val controls only.

ConclusionWe report that chronic CORT exposure interacts with the BDNF
Val66Met polymorphism to selectively modify affective- and anxiety-related
behavior. This novel gene-environment interaction highlights how affective- and
anxiety-related behavior is variably regulated by both BDNF and CORT exposure,
having implications for the treatment and prevention of stress-inducible psychiatric
disorders.